Project Summary Metastatic melanoma was until recently considered an untreatable disease, but the discovery of small molecules that inhibit oncogenic BRAF(V600E) and approaches that unleash the immune system against tumors have brought hope to melanoma patients. Not every patient will have meaningful therapeutic benefit from these treatments and durable disease remission remains elusive for most. Among the causes of the failure to respond or early relapse is a dynamic cancer cell heterogeneity that facilitates outgrowth of therapy resistant tumors with enhanced malignancy traits. In order to extend the use of current therapies, we propose to identify alternative molecular targets that could be harnessed for combinatorial treatment exploit and might hold promise for sustainable therapeutic benefit. Specifically, whether metabolic and epigenetic processes provide collateral dependencies within highly metastatic and chronic BRAF-targeted drug-adapted melanomas is largely unknown. To this end, a third of melanomas display heightened expression of the transcriptional coactivator PGC1? that integrates mitochondrial biogenesis and bioenergetic activity to ensure cellular survival. Previously we found an inverse functional relationship between PGC1? expression and vertical growth phase within primary melanoma that associates with poor patient prognosis, and genetic targeting of PGC1? provoked enhanced metastatic traits in cell line models. Consistent with a functional role for adaptive expression of PGC1? and enhanced malignancy traits, our current preliminary data supports that chronic adaptation to BRAF-targeted drugs silences PGC1? expression through altered histone marks across its promoter region. We now propose to seek the molecular mechanisms that attenuate PGC1? expression that links enhanced metastatic spread and chronic adaptation to BRAF-targeted drugs. In an integrated study plan that includes clinical melanoma specimens, established cell lines and in vivo tumor modeling, the experimental design is focused on two aims: 1) to determine epigenetic mechanisms that silence PGC1? expression during chronic adaptation to targeted BRAF(V600E) treatment; and 2) to identify collateral metabolic and epigenetic vulnerabilities arising from chronic adaptation to targeted BRAF(V600E) treatment. Outcomes from these studies will identify metabolites and epigenetic regulators that provoke vulnerabilities within alternate PGC1?- dependent epigenetic states. Successful completion of the proposed study plan may help predict patients at heightened clinical risk as well as provide means to break chronic adaptation to BRAF-targeted drugs.